ABSTRACT

Context An unexplained increase in the risk of Guillain-Barré syndrome
(GBS) occurred among recipients of the swine influenza vaccine in 1976-1977.
Guillain-Barré syndrome remains the most frequent neurological condition
reported after influenza vaccination to the Vaccine Adverse Events Reporting
System (VAERS) since its inception in 1990.

Objective To evaluate trends of reports to VAERS of GBS following influenza vaccination
in adults.

Design, Setting, and Participants VAERS is the US national spontaneous reporting system for adverse events
following vaccination. Reports of GBS in persons 18 years or older following
influenza vaccination were evaluated for each influenza season from July 1,
1990, through June 30, 2003. The number of people vaccinated was estimated
from the National Health Interview Survey and US census data. Beginning in
1994, active follow-up was conducted to verify GBS diagnosis and obtain other
clinical details.

Main Outcome Measure Reporting rates of GBS following influenza vaccination over time.

Results From July 1990 through June 2003, VAERS received 501 reports of GBS
following influenza vaccination in adults. The median onset interval (13 days)
was longer than that of non-GBS reports of adverse events after influenza
vaccine (1 day) (P<.001). The annual reporting
rate decreased 4-fold from a high of 0.17 per 100 000 vaccinees
in 1993-1994 to 0.04 in 2002-2003 (P<.001). A
GBS diagnosis was confirmed in 82% of reports. Preceding illness within 4
weeks of vaccination was identified in 24% of reported cases.

Conclusions From 1990 to 2003, VAERS reporting rates of GBS after influenza vaccination
decreased. The long onset interval and low prevalence of other preexisting
illnesses are consistent with a possible causal association between GBS and
influenza vaccine. These findings require additional research, which can lead
to a fuller understanding of the causes of GBS and its possible relationship
with influenza vaccine.

Figures in this Article

Guillain-Barré syndrome (GBS) is an acute, immune-mediated paralytic
disorder of the peripheral nervous system.1 Concerns
about the risk of developing GBS following influenza vaccination have been
present since an association was first noticed during the 1976-1977 A/New
Jersey (“swine influenza”) season.2 A
statistically significant elevated risk of GBS was found in swine flu vaccinees
relative to nonvaccinees within 6 to 8 weeks after vaccination.3- 7 Evidence
for a relationship between GBS and other influenza vaccines, however, is less
clear.8 After 1977, most studies of GBS and
influenza vaccines found low relative risks that were not statistically significant.9- 12 A
study of the 1992-1993 and 1993-1994 seasons found a combined relative risk
for GBS among influenza vaccine recipients of 1.7 (95% confidence interval,
1.0-2.8; P = .04) during the 6 weeks following
vaccination.13

Because the antigenic composition of influenza vaccine varies from year
to year and the potential for risk of GBS also varies, we have been monitoring
trends in reports of GBS to the Vaccine Adverse Event Reporting System (VAERS)
following influenza vaccination since the system’s inception in 1990.14- 17 Herein
we report our analysis of those trends.

METHODS

VAERS is a national postmarketing spontaneous reporting system for vaccine
adverse events following receipt of US-licensed vaccines.14- 17 We
selected all VAERS reports of GBS following influenza vaccination in persons
at least 18 years old who were vaccinated between July 1990 and June 2003.

To estimate the proportion of the population receiving influenza vaccination
by age and season, we used data from the National Health Interview Survey.18 Census estimates of the population19 by
age group were multiplied by the proportion of people receiving influenza
vaccine in the same age groups to determine the number of people vaccinated.
We calculated age-specific reporting rates by dividing the number of VAERS
reports of GBS following influenza vaccination by the estimated number of
people who received influenza vaccine in each age group and season. We compared
reporting rates of GBS following influenza vaccination with all other non-GBS
adverse event reports by influenza season and onset interval, where influenza
season was defined as July 1 through June 30 and onset interval as the number
of days from the vaccination date to the date of reported symptom onset.

We performed Poisson regression analyses for linear trend to assess
reporting trends with adjustments for age and sex, as appropriate, for all
GBS reports and for those that were verified on follow-up. Statistical analysis
was performed with the PROC GENMOD module in SAS version 8.2 (SAS Institute
Inc, Cary, NC). Statistical significance was set a priori as P<.05.

During each influenza season since 1994, we conducted active follow-up
of all GBS reports following influenza vaccination to verify the diagnosis
and to obtain additional clinical information (eg, prior illness within 4
weeks before onset of GBS, history of prior influenza vaccination, and prior
GBS occurrence).

To determine how the trends in GBS reporting to VAERS compare with GBS
trends in the general population, we analyzed hospital discharge data from
the Nationwide Inpatient Sample.20 We analyzed
GBS primary hospital discharge diagnoses (International
Classification of Diseases, Ninth Revision code 357.00) and used
annual census data of the population of participating states to calculate
annual GBS hospital discharge rates.

RESULTS

From July 1990 through June 2003, VAERS received 501 reports of GBS
following influenza vaccination in persons at least 18 years old. Annual reporting
rates of GBS per 100 000 influenza vaccinations declined (P<.001) from a high of 0.17 in 1993-1994 to a low of
0.04 in 2002-2003 (Figure 1). In contrast,
there was a significant (P<.001) increase in the
reporting rates of non-GBS adverse events after influenza vaccination. Reporting
rates of GBS decreased in all age groups (Figure
2 and Table), whereas age
group–specific trends varied for the non-GBS reports (Table).

Reports of GBS had a different pattern of onset intervals from non-GBS
reports, with the median onset interval for GBS reports (13 days) being longer
than that of non-GBS reports after influenza vaccination (1 day) (range, 0-741
days) (P<.001). Fifty-nine percent of all GBS
reports for which the onset interval was available (286/486) noted symptom
onset within 0 to 14 days following vaccination, while 94.5% of all non-GBS
reports noted symptom onset within the same time interval (Figure 3).

In the GBS follow-up study during 1994 through 2003, we obtained information
for 323 GBS reports. We excluded reports for persons lost to follow-up (n=33)
and those with a non-GBS diagnosis (n=26) and analyzed the remaining 264 confirmed
GBS reports (82%). The trend was similar to all GBS reports. The follow-up
study also found that a preceding illness within 4 weeks of vaccination was
present in 24% of reported cases (n=76), and 105 had received influenza vaccine
in the previous seasons.

In the analysis of hospital discharge trends for GBS using Nationwide
Inpatient Sample data, we found that from 1989 to 1997 discharge rates were
relatively unchanged, fluctuating around 3.2 per 100 000 population
(P = .11). From 1997 through 2001, however,
the hospital discharge rate for GBS decreased from 3.1 to 2.5 per 100 000
population (P = .009).

COMMENT

Since the inception of VAERS in 1990, we have observed extensive variability
in reporting rates of GBS after influenza vaccination but most notably a marked
decline since the 1996-1997 season. This pattern was not observed with non-GBS
reports. Possible explanations for these findings include changes in vaccine
coverage, reporting artifacts, general decline in GBS overall, or changes
in the influenza vaccine that could be causally related to GBS.

Influenza vaccination coverage in adults increased 2-fold from 1988-1989
to 1999-2000 among healthy adults and high-risk persons older than 18 years.21 If younger people who are at decreased risk for GBS
were being vaccinated, it could have resulted in decreased reporting rates
of GBS after influenza vaccination. This is not a likely explanation for our
findings, however, since we found decreases in GBS reporting rates in all
age groups and we adjusted the annual rates for age.

Like all passive surveillance systems, VAERS is subject to underreporting,
differential reporting, and variability in report quality and completeness.22 Reporting to VAERS is more likely when the adverse
event is severe or occurs shortly after vaccination, the vaccine is newly
introduced, and when there has been publicity about a vaccine adverse event.16,17,23,24 We
tried to address concerns about the quality of the VAERS data by performing
a follow-up study in which we were able to confirm a diagnosis of GBS in 82%
of the reports, and analyses restricted to confirmed reports did not alter
our findings. We also found similar results in a subanalysis restricted to
cases with onset less than 6 weeks following vaccination and thus more likely
to have been causally related to vaccination. We do not think that diminishing
awareness of GBS following influenza vaccination is a likely explanation of
our findings because a major study that found an increased risk of GBS following
influenza vaccination was published in 1998.13 Moreover,
reporting of non-GBS adverse events after influenza vaccination did not decrease
over time.

At least 2 of our findings suggest that many of the reports to VAERS
of GBS following influenza vaccination were not entirely coincidental. First,
the reported onset interval differed for GBS reports compared with other influenza
vaccine VAERS reports (Figure 3). Second,
the relatively low prevalence of antecedent illness in our study (24%) was
similar to the findings of the swine flu investigations (33% in vaccinated
cases compared with 62% in unvaccinated cases). During the swine flu investigations,
the markedly lower proportion of vaccinated compared with unvaccinated cases
with a history of a recent illness provided strong evidence for a causal relationship
between influenza vaccination and GBS, suggesting that vaccine replaced acute
illness as a trigger of GBS.2

The significant decrease in GBS hospital discharges in the general population
from 1997 through 2001 in the Nationwide Inpatient Sample suggests that the
decrease in GBS reports to VAERS may be due at least in part to a general
decline in the background rate of GBS. This is unlikely to be the only explanation
since the decline in GBS reports to VAERS following influenza vaccination
after 1996 (60%) was much steeper than the corresponding decline in Nationwide
Inpatient Sample GBS hospital discharge rates (20%). However, both of these
decreases may be related.

Influenza vaccines have traditionally been made in chicken eggs, and Campylobacter is an endemic infection among chickens and
a known cause of GBS.25,26 The
Food-borne Diseases Active Surveillance Network (FoodNet) has found that from
1996 to 2003, laboratory-confirmed Campylobacter infections
in humans decreased 28% in the United States due to enhanced food safety interventions.27 Interestingly, 1996-1997 is also when both the decline
in GBS reports to VAERS and GBS hospitalizations in the Nationwide Inpatient
Sample began. These data raise intriguing questions about whether GBS among
influenza vaccinees may be related to Campylobacter infection.
Additional research to unravel this possibility may lead to a fuller understanding
of the causes of GBS and its possible relationship with influenza vaccine.

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